Method for protecting normal cells from cytotoxicity of chemotherapeutic agents

ABSTRACT

Pre-treatment with α,β unsaturated aryl sulfones protects normal cells from the cytotoxic side effects of two classes of anticancer chemotherapeutics. Administration of a cytoprotective sulfone compound to a patient prior to anticancer chemotherapy with a mitotic phase cell cycle inhibitor or topoisomerase inhibitor reduces or eliminates the cytotoxic side effects of the anticancer agent on normal cells. The cytoprotective effect of the α,β unsaturated aryl sulfone allows the clinician to safely increasing the dosage of the anticancer chemotherapeutic.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation of U.S. patent applicationSer. No. 09/689,281, filed Oct. 11, 2000, which claimed pursuant to 35U.S.C. 119(e) the benefit of the filing date of provisional applicationSer. No. 60/159,123, filed Oct. 12, 1999. The entire disclosures of theaforesaid applications are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The invention relates to the field of anticancer chemotherapy,and cytoprotective agents administered before, during or afteranticancer chemotherapy to protect the normal cells of the patient fromthe cytotoxic effects of anticancer chemotherapeutics.

BACKGROUND OF THE INVENTION

[0003] Experimental chemotherapy has been the mainstay of treatmentoffered to patients diagnosed with surgically unresectable advancedcancers, or cancers refractory to standard chemotherapy and radiationtherapy. Of the more effective classes of drugs, curative properties arestill limited. This is because of their relatively narrow therapeuticindex, restricted dosage, delayed treatments and a relatively largeproportion of only partial tumor reductions. This state is usuallyfollowed by recurrence, increased tumor burden, and drug resistanttumors.

[0004] Several cytoprotective agents have been proposed to enhance thetherapeutic index of anticancer drugs. For methotrexate toxicity, suchagents include asparaginase, leucovorum factor, thymidine, andcarbipeptidase. Because of the extensive use of anthracyclines, specificand non-specific cytoprotective agents have been proposed which havevarying degrees of efficacy; included are corticosteroids, desrazoxaneand staurosporin. The latter is of interest in that it includes a G1/Srestriction blockade in normal cells. (Chen et al., Proc AACR 39:4436A,1998).

[0005] Cisplatin is widely used and has a small therapeutic index whichhas spurred investigation and search of cytoprotectants. Among thecytoprotectants for cisplatin with clinical potential are mesna,glutathione, Na-thiosulfate, and amifostine (Griggs, Leuk. Res. 22 Suppl1:S27-33, 1998; List et al., Semin. Oncol. 23(4 Suppl 8):58-63, 1996;Taylor et al., Eur. J. Cancer 33(10):1693-8, 1997). None of these orother proposed cytoprotectants such as oxonic acid for fluoropyrimidinetoxicity, or prosaptide for paclitaxel PC12 cell toxicity, appears tofunction by a mechanism which renders normal replicating cells into aquiescent state.

[0006] What is needed are cytoprotective agents which are effective inprotecting animals, inclusive of humans, from the cytotoxic side effectsof chemotherapeutic agents.

[0007] Unrelated to the foregoing, styryl sulfones having pharmaceuticalutility as anticancer agents have been reported in WO/99/18068, theentire disclosure of which is incorporated herein by reference. Thecompounds inhibit tumor cell growth by inducing tumor cell death withoutkilling normal cells. The styryl sulfones are effective in a broad rangeof tumor types. Without wishing to be bound by any theory, it isbelieved that the styryl sulfones affect the Mitogen Activated ProteinKinase (MAPK) signal transduction pathway, thereby affecting tumor cellgrowth and viability.

SUMMARY OF THE INVENTION

[0008] It is an object of the invention to provide compositions andmethods for protecting animals, inclusive of humans, from the cytotoxicside effects of chemotherapeutic agents, particularly mitotic phase cellcycle inhibitors and topoisomerase inhibitors, used in the treatment ofcancer and other proliferative disorders.

[0009] It is an object of the invention provide a method for treatingcancer or other proliferative disorder which reduces or eliminatescytotoxic effects on normal cells.

[0010] It is an object of the invention to enhance the effects ofchemotherapeutic agents, particularly mitotic phase cell cycleinhibitors and topoisomerase inhibitors, used for the treatment ofcancer or other proliferative disorders.

[0011] It is an object of the present invention to provide a therapeuticprogram for treating cancer or other proliferative disorder whichincludes administration of a cytoprotective compound prior toadministration of a chemotherapeutic agent, which cytoprotectivecompound induces a reversible cycling quiescent state in non-tumoredtissues.

[0012] It is an object of the invention to provide a method for safelyincreasing the dosage of chemotherapeutic agents, particularly mitoticphase cell cycle inhibitors and topoisomerase inhibitors, used in thetreatment of cancer and other proliferative disorders.

[0013] According to the present invention, a method for protecting ananimal from cytotoxic side effects of the administration of a mitoticphase cell cycle inhibitor or a topoisomerase inhibitor comprisesadministering to the animal, in advance of administration of theaforesaid inhibitor, an effective amount of at least one cytoprotectiveα,β unsaturated aryl sulfone compound. The term “animal” is meant toembrace human beings, as well as non-human animals.

[0014] By “α,β unsaturated aryl sulfone compound” as used herein ismeant a chemical compound containing one or more α,β unsaturated arylsulfone groups:

[0015] wherein Q₂ is substituted or unsubstituted aryl, and the hydrogenatoms attached to the α and β carbons are optionally replaced by otherchemical groups.

[0016] By “substituted” means that an atom or group of atoms hasreplaced hydrogen as the substituent attached to a ring atom. The degreeof substitution in a ring system may be mono-, di-, tri- or highersubstitution.

[0017] The term “aryl”, alone or in combination, means a carbocyclicaromatic system containing one, two, or more rings wherein such ringsmay be attached together in a pendent manner or may be fused. The term“aryl” is intended to include not only aromatic systems containing onlycarbon ring atoms but also systems containing one or more non-carbonatoms as ring atoms. Such systems may be known as “heteroaryl” systems.The term “aryl” is thus deemed to include “heteroaryl”. Heteroarylgroups include, for example, pyridyl, thienyl, furyl, thiazolyl,pyrrolyl, and thienyl-1,1-dioxide The heterocyclic radical may besubstituted or unsubstituted. The term “aryl” is not limited to ringsystems with six members.

[0018] According to one embodiment, the α,β unsaturated aryl sulfonegroup is a styryl sulfone group:

[0019] wherein the hydrogen atoms attached to the α and β carbons areoptionally replaced by other chemical groups, and the phenyl ring isoptionally substituted.

[0020] By “styryl sulfone” or “styryl sulfone compound” or “styrylsulfone therapeutic” as used herein is meant a chemical compoundcontaining one or more such styryl sulfone groups.

[0021] According to another embodiment of the invention, a method oftreating an individual for cancer or other proliferative disorder isprovided. The method comprises administering to the animal an effectiveamount of at least one mitotic phase cell cycle inhibitor ortopoisomerase inhibitor, and administering before the inhibitor, aneffective amount of at least one cytoprotective α,β unsaturated arylsulfone compound.

[0022] By “effective amount” of the mitotic phase cell cycle inhibitoror topoisomerase inhibitor is meant an amount of said inhibitoreffective in killing or reducing the proliferation of cancer cells in ahost animal. By “effective amount” of the cytoprotective α,β unsaturatedaryl sulfone compound is meant an amount of compound effective to reducethe toxicity of the mitotic phase cell cycle inhibitor or topoisomeraseinhibitor on normal cells of the animal.

[0023] The α,β unsaturated aryl sulfone cytoprotective compounds arecharacterized by cis-trans isomerism resulting from the presence of adouble bond. Steric relations around a double bond are designated as AZ@or AE@. Both configurations are included in the scope of “α,βunsaturated aryl sulfone”:

[0024] According to one embodiment, the α,β unsaturated aryl sulfonecompound is a compound of the formula I:

[0025] wherein:

[0026] n is one or zero;

[0027] Q₁ and Q₂ are, same or different, are substituted orunsubstituted aryl.

[0028] Preferably, n in formula I is one, that is, the compoundscomprise α,β unsaturated benzylsulfones, e.g. styryl benzylsulfones.

[0029] According to one sub-embodiment, n is preferably one and:

[0030] Q₁ is selected from the group consisting of substituted andunsubstituted phenyl, 1-naphthyl, 2-naphthyl, 9-anthryl and an aromaticradical of formula II:

[0031]  wherein

[0032] n₁ is 1 or 2,

[0033] Y₁ and Y₂ are independently selected from the group consisting ofhydrogen, halogen, and nitro, and

[0034] X₁ is selected from the group consisting of oxygen, nitrogen,sulfur and

[0035] and

[0036] Q₂ is selected from the group consisting of substituted andunsubstituted phenyl, 1-naphthyl, 2-naphthyl, 9-anthryl and an aromaticradical of formula III:

[0037]  wherein

[0038] n₂ is 1 or 2,

[0039] Y₃ and Y₄ are independently selected from the group consisting ofhydrogen, halogen, and nitro, and

[0040] X₂, X₃ and X₄ are independently selected from the groupconsisting of carbon, oxygen, nitrogen, sulfur and

[0041]  provided that not all of X₂, X₃ and X₄ may be carbon.

[0042] According to one preferred embodiment according to formula 1, Q₁and Q₂ are selected from substituted and unsubstituted phenyl.

[0043] Preferred compounds where Q₁ and Q₂ are selected from substitutedand unsubstituted phenyl comprise compounds of the formula IV:

[0044] wherein:

[0045] R₁ through R₁₀ are independently selected from the groupconsisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, nitro,cyano, carboxy, hydroxy, phosphonato, amino, sulfamyl, acetoxy,dimethylamino(C2-C6 alkoxy), C1-C6 trifluoroalkoxy and trifluoromethyl.

[0046] In one embodiment, compounds of formula IV are at leastdi-substituted on at least one ring, that is, at least two of R₁ throughR₅ and/or at least two of R₅ through R₁₀, are other than hydrogen. Inanother embodiment, compounds of formula IV are at least trisubstitutedon at least one ring, that is, at least three of R₁ through R₅ and/or atleast three of R₅ through R₁₀, are other than hydrogen.

[0047] In one embodiment, the cytoprotective compound has the formula V:

[0048] wherein R₁, R₂, R₃ and R₄ are independently selected from thegroup consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, nitro,cyano, carboxy, hydroxy and trifluoromethyl.

[0049] According to a particularly preferred embodiment of theinvention, the cytoprotective compound is according to formula V, and R₁and R₂ are independently selected from the group consisting of hydrogen,chlorine, fluorine, bromine, cyano, and trifluoromethyl; and R₃ and R₄are independently selected from the group consisting of hydrogen,chlorine, fluorine and bromine.

[0050] Preferred compounds according to formula V having theE-configuration include, but are not limited to,(E)-4-fluorostyryl-4-chlorobenzylsulfone;(E)-4-chlorostyryl-4-chlorobenzylsulfone;(E)-2-chloro-4-fluorostyryl-4-chlorobenzylsulfone;(E)-4-carboxystyryl-4-chlorobenzyl sulfone;(E)-4-fluorostyryl-2,4-dichlorobenzylsulfone;(E)-4-fluorostyryl-4-bromobenzylsulfone;(E)-4-chlorostyryl-4-bromobenzylsulfone;(E)-4-bromostyryl-4-chlorobenzylsulfone;(E)-4-fluorostyryl-4-trifluoromethylbenzylsulfone;(E)-4-fluorostyryl-3,4-dichlorobenzylsulfone;(E)-4-fluorostyryl-4-cyanobenzylsulfone;(E)-2,4-dichloro-4-chlorobenzylsulfone; and(E)-4-chlorostyryl-2,4-dichlorobenzylsulfone.

[0051] According to another embodiment, compounds of formula I have theZ configuration wherein R₁ and R₃ are hydrogen, and R₂ and R₄ areselected from the group consisting of 4-Cl, 4-F and 4-Br. Such compoundsinclude, for example, (Z)-4-chlorostyryl-4-chlorobenzylsulfone;(Z)-4-chlorostyryl-4-fluorobenzylsulfone;(Z)-4-fluorostyryl-4-chlorobenzylsulfone;(Z)-4-bromostyryl-4-chlorobenzylsulfone; and(Z)-4-bromostyryl-4-fluorobenzylsulfone.

[0052] According to another embodiment, the cytoprotective α,βunsaturated aryl sulfone compound is a compound of the formula VI:

[0053] wherein

[0054] R₁, R₂, R₃, and R₄ are independently selected from the groupconsisting of hydrogen, halogen, C1-8 alkyl, C1-8 alkoxy, nitro, cyano,carboxyl, hydroxyl, and trifluoromethyl.

[0055] In one embodiment, R₁ in formula VI is selected from the groupconsisting of hydrogen, chlorine, fluorine and bromine; and R₂, R₃ andR₄ are hydrogen.

[0056] According to yet another embodiment, the cytoprotective α,βunsaturated aryl sulfone compound is a compound of the formula VII:

[0057] wherein

[0058] Q₃, Q₄ and Q₅ are independently selected from the groupconsisting of phenyl and mono-, di-, tri-, tetra- and penta-substitutedphenyl where the substituents, which may be the same or different, areindependently selected from the group consisting of halogen, C1-C8alkyl, C1-C8 alkoxy, nitro, cyano, carboxy, hydroxy, phosphonato, amino,sulfamyl, acetoxy, dimethylamino(C2-C6 alkoxy), C1-C6 trifluoroalkoxyand trifluoromethyl.

[0059] According to one sub-embodiment of formula VII, thecytoprotective α,β unsaturated aryl sulfone compound is a compound ofthe formula VIIa:

[0060] wherein

[0061] R₁ and R₂ are independently selected from the group consisting ofhydrogen, halogen, C1-C8 alkyl, C1-8 alkoxy, nitro, cyano, carboxyl,hydroxyl, and trifluoromethyl; and

[0062] R₃ is selected from the group consisting of unsubstituted phenyl,mono-substituted phenyl and di-substituted phenyl, the substituents onthe phenyl ring being independently selected from the group consistingof halogen and C1-8 alkyl.

[0063] Preferably, R₁ in formula VIIa is selected from the groupconsisting of fluorine and bromine; R₂ is hydrogen; and R₃ is selectedfrom the group consisting of 2-chlorophenyl, 4-chlorophenyl,4-fluorophenyl, and 2-nitrophenyl.

[0064] A preferred cytoprotective styryl sulfone according to formulaVIIa is the compound wherein R₁ is fluorine, R₂ is hydrogen and R₃ isphenyl, that is, the compound2-(phenylsulfonyl)-1-phenyl-3-(4-fluorophenyl)-2-propen-1-one.

[0065] By “dimethylamino(C2-C6 alkoxy)” is meant (CH₃)₂N(CH₂)_(n)O—wherein n is from 2 to 6. Preferably, n is 2 or 3. Most preferably, n is2, that is, the group is the dimethylaminoethoxy group, that is,(CH₃)₂NCH₂CH₂O—.

[0066] By “phosphonato” is meant the group —PO(OH)₂.

[0067] By “sulfamyl” is meant the group —SO₂NH₂.

[0068] Where a substituent on an aryl nucleus is an alkoxy group, thecarbon chain may be branched or straight, with straight being preferred.Preferably, the alkoxy groups comprise C1-C6 alkoxy, more preferablyC1-C4 alkoxy, most preferably methoxy.

DESCRIPTION OF THE FIGURES

[0069]FIG. 1 shows the plating efficiency of normal human fibroblasts(HFL-1) treated with various concentrations of the styryl sulfone(E)-4-fluorostyryl-4-chlorobenzylsulfone. The cells were incubated withthe indicated concentration of the styryl sulfone for 24 hours, washedthree times and harvested by trypsinization. Cells were plated atvarious dilutions to determine colony-forming ability.

[0070]FIG. 2 shows the effect of long term exposure of HFL-1 to(E)-4-fluorostyryl-4-chlorobenzylsulfone. Cells were exposed to either2.5 or 5.0 μM of the styryl sulfone for 96 hours and counted.

[0071]FIG. 3 is a graph of the effect of paclitaxel on HFL-1 cells whichwere either pre-treated with (E)-4-fluorostyryl-4-chlorobenzylsulfoneand then exposed to paclitaxel, or treated simultaneously with bothagents. Cells were enumerated 96 hours after exposure to paclitaxel.

[0072]FIG. 4 is a plot of the effect of vincristine on HFL-1 cellsVincristine toxicity is abrogated by styryl sulfone treatment. NormalHFL cells were treated with 0 to 0.250 nM vincristine and 2.0 μM(E)-4-fluorostyryl-4-chlorobenzylsulfone as indicated. Cell viabilitywas assessed 96 hours after vincristine was added. “V”, vincristinealone; “A→V”, styryl sulfone followed by vincristine 24 hours later;“A+V”, simultaneous styryl sulfone and vincristine treatment; “V→A”,vincristine followed by styryl sulfone 24 hours later.

[0073]FIG. 5 shows the effect of the styryl sulfone(E)-4-fluorostyryl-4-chlorobenzylsulfone in protecting mice frompaclitaxel cytotoxicity. The styryl sulfone was given 24 hours beforepaclitaxel, 4 hours before paclitaxel, or simultaneously withpaclitaxel. Control animals received paclitaxel alone or styryl sulfonealone. Mortality was assessed 48 after paclitaxel injection.

[0074]FIG. 6 is similar to FIG. 5, except that mortality was assessed144 hours post paclitaxel administration.

DETAILED DESCRIPTION OF THE INVENTION

[0075] According to the present invention, certain α,β unsaturated arylsulfones are administered with the aim of reducing or eliminatingadverse effects of anticancer treatment with chemotherapeutic agentswhich comprise mitotic phase cell cycle inhibitors.

[0076] The usual description of the cell cycle describes the cycle interms of a series of phases—interphase and M (mitotic) phase—and thesubdivision of interphase into the times when DNA synthesis isproceeding, known as the S-phase (for synthesis phase), and the gapsthat separate the S-phase from mitosis. G1 is the gap after mitosis butbefore DNA synthesis starts, and G2 is the gap after DNA synthesis iscomplete before mitosis and cell division. Interphase is thus composedof successive G1, S and G2 phases, and normally comprises 90% or more ofthe total cell cycle time. The M phase consists of nuclear division(mitosis) and cytoplasmic division (cytokinesis). During the early partof the M phase, the replicated chromosomes condense from their extendedinterphase condition. The nuclear envelope breaks down, and eachchromosome undergoes movements that result in the separation of pairs ofsister chromatids as the nuclear contents are divided. Two new nuclearenvelopes then form, and the cytoplasm divides to generate two daughtercells, each with a single nucleus. This process of cytokinesisterminates the M phase and marks the beginning of the interphase of thenext cell cycle. The daughter cells resulting from completion of the Mphase begin the interphase of a new cycle.

[0077] By “mitotic phase cell cycle inhibitor” is meant a chemical agentwhose mechanism of action includes inhibition of a cell's passagethrough any portion of the mitotic (M) phase of the cell cycle. Suchagents include, by way of example and not limitation, taxanes, such aspaclitaxel and its analogs; vinca alkaloids such as vincristine andvinblastine; colchicine; estramustine; and naturally occurringmacrolides such as rhizoxin, maytansine, ansamitocin P-3, phomopsin A,dolastatin 10 and halichrondin B.

[0078] Paclitaxel is an anti-mitotic drug presently used as an initialtreatment for ovarian, breast and lung cancer, with moderate success.Vincristine is a well-established anti-mitotic drug widely used for thetreatment of breast cancer, Hodgkin's lymphoma and childhood cancers.

[0079] The topoisomerases constitute a group of enzymes that catalyzethe conversion of DNA from one topological form to another byintroducing transient breaks in one or both strands of a DNA duplex.Topological isomers are molecules that differ only in their state ofsupercoiling. Type I topoisomerase cuts one strand of DNA and relaxesnegatively supercoiled DNA, but does not act on positively supercoiledDNA. Type II topoisomerase cuts both strands of DNA and increases thedegree of negative supercoiling in DNA. By “topoisomerase inhibitor” ismeant a chemical agent whose mechanism of action includes interferingwith the function of a topoisomerase.

[0080] Inhibitors of topoisomerase I include, for example, adriamycinand etoposide. Inhibitors of topoisomerase II include, for example,camptothecin, irinotecan and topotecan.

[0081] The α,β unsaturated aryl sulfones differ from other knowncytoprotective agents in that they not only protect normal cells, butare also operationally cytotoxic in tumor cells. In normal cells, theα,β unsaturated aryl sulfones induce a reversible resting staterendering the normal cells relatively refractory to the cytotoxic effectof mitotic phase cell cycle inhibitors and topoisomerase inhibitors.Data indicating the cytotoxic effect of the α,β unsaturated aryl sulfonecompounds on tumor cells is set forth in PCT/US/98/20580;PCT/US00/08565; and in the following commonly assigned U.S. patentapplications Ser. Nos. 60/127,683, filed Apr. 2, 1999; 60/143,975, filedJul. 15, 1999; 09/282,855, filed Mar. 31, 1999; and 60/197,368, filedApr. 14, 2000. The entire disclosures of the aforesaid PCT and U.S.patent applications are incorporated herein by reference. It is believedthat the α,β unsaturated aryl sulfones, and particularly the styrylsulfones, are the first compounds which are both cytoprotective innormal cells and toxic in cancer cells.

[0082] As demonstrated herein, normal human fibroblasts exposed to α,βunsaturated aryl sulfones in vitro exhibit transiently reducedreplication rates. When the same cells are then exposed to a mitoticphase cell cycle inhibitor such as paclitaxel, the cells are protectedfrom the toxic effects of the inhibitor. Simultaneous exposure of α,βunsaturated aryl sulfone and the inhibitor does not result inprotection. The precise cytoprotective mechanism of action of the α,βunsaturated aryl sulfones on normal tissues is unknown. However, basedon experimental models, and without wishing to be bound by any theory,these compounds may affect several elements in normal cells inducing areversible quiescent cell-cycling state in which transit throughmitosis, and many of the changes necessary for such passage, are downregulated, inactivated or absent. Tumor cells appear to be refractory tothis effect of the α,β unsaturated aryl sulfones and in fact continuecycling with readily activated programmed cell death pathways. Accordingto other possible mechanisms of protection, anticancer agent-inducedproinflammatory cytokine release from monocytes or macrophages,activation of JNK-1 death pathway induction, and P34Cdc2 kinase may berendered innocuous by pre-exposure to α,β unsaturated aryl sulfones.

[0083] In tumored cells, α,β unsaturated aryl sulfones exhibitcontrasting characteristics. They are cytotocidal at a low concentrationrather than being reversible cytostatic, even at high concentrations.The α,β unsaturated aryl sulfones impact on normal cells is to cause atransitory cycling arrest. Paclitaxel cytotoxic effects includeproinflammatory cytokine release of IL-1, TNF, and nitric oxide (Kirikaeet al. Biochem Biophys Res Commun. 245:698-704, 1998; White et al.Cancer Immunol. Immunoth. 46:104-112, 1998). Its major effect is mitoticblockade, and induction of c-Jun NHα-terminal kinase/AP-1 deathpathways. (Lee et al., J. Biol Chem 273:28253-28260, 1998; Amato et al.,Cancer Res. 58:241-247, 1998). As cytoprotective agents against thetoxicity of paclitaxel, the α,β unsaturated aryl sulfones presumablyalso induce a direct or indirect biochemical blockade ofmacrophage/monocyte response to paclitaxel in normal cells, andinterfere with the cell death signaling pathway.

[0084] The schedule of administration of the cytotoxic drug, i.e.,mitotic phase cell cycle inhibitor or topoisomerase inhibitor, can beany schedule with the stipulation that α,β unsaturated aryl sulfone isadministered prior to the cytotoxic drug. The sulfone should beadministered far enough in advance of the cytotoxic drug such that theformer is able to reach the normal cells of the patient in sufficientconcentration to exert a cytoprotective effect on the normal cells. Inone embodiment, the sulfone is administered at least about 4 hoursbefore administration of the cytotoxic drug. The sulfone may beadministered as much as about 48 hours, preferably no more than about 36hours, prior to administration of the cytotoxic drug. Most preferably,the sulfone is administered about 24 hours before the cytotoxic drug.The sulfone may be administered more or less than 24 hours before thecytotoxic effect, but the protective effect of the α,β unsaturated arylsulfones is greatest when administered about 24 hours before thecytotoxic drug. One or more cytotoxic drugs may be administered.Similarly, one or more α,β unsaturated aryl sulfones may be combined.

[0085] Where the cytotoxic drug or drugs is administered in serialfashion, it may prove practical to intercalate sulfones within theschedule with the caveat that a 4-48 hour period, preferably a 12-36hour period, most preferably a 24 hour period, separates administrationof the two drug types. This strategy will yield partial to completeeradication of cytotoxic drug side effects without affecting anticanceractivity.

[0086] For example, the mitotic inhibitor may be given daily, or everyfourth day, or every twenty-first day. The sulfone may be given 24 hoursprevious to each round of inhibitor administration, both as acytoprotective agent and as an antitumor agent.

[0087] It may be appreciated that by “administered” is meant the act ofmaking drug available to the patient such that a physiological effect isrealized. Thus, contemplated within the scope of the present inventionis the instillation of drug in the body of the patient in a controlledor delayed release formulation, with systemic or local release of thedrug to occur at a later time. Thus, a depot of sulfone maybeadministered to the patient more than 48 hours before the administrationof cytotoxic drug provided that at least a portion of the sulfone isretained in the depot and not released until the 48 hour window prior tothe administration of the cytotoxic drug.

[0088] The α,β unsaturated aryl sulfone compound may be administered byany route which is sufficient to bring about the desired cytoprotectiveeffect in the patient. Routes of administration include enteral, such asoral; and parenteral, such as intravenous, intraarterial, intramuscular,intranasal, rectal, intraperitoneal, subcutaneous and topical routes.

[0089] The α,β unsaturated aryl sulfone may be administered in the formof a pharmaceutical composition, in combination with a pharmaceuticallyacceptable carrier. The active ingredient in such formulations maycomprise from 0.1 to 99.99 weight percent. By “pharmaceuticallyacceptable carrier” is meant any carrier, diluent or excipient which iscompatible with the other ingredients of the formulation and todeleterious to the recipient.

[0090] The active agent may be formulated into dosage forms according tostandard practices in the field of pharmaceutical preparations. SeeAlphonso Gennaro, ed., Remington's Pharmaceutical Sciences, 18th Ed.,(1990) Mack Publishing Co., Easton, Pa. Suitable dosage forms maycomprise, for example, tablets, capsules, solutions, parenteralsolutions, troches, suppositories, or suspensions.

[0091] For parenteral administration, the α,β unsaturated aryl sulfonemay be mixed with a suitable carrier or diluent such as water, an oil,saline solution, aqueous dextrose (glucose) and related sugar solutions,or a glycol such as propylene glycol or polyethylene glycol. Solutionsfor parenteral administration preferably contain a water soluble salt ofthe active agent. Stabilizing agents, antioxidizing agents andpreservatives may also be added. Suitable antioxidizing agents includesulfite, ascorbic acid, citric acid and its salts, and sodium EDTA.Suitable preservatives include benzalkonium chloride, methyl- orpropyl-paraben, and chlorbutanol. The composition for parenteraladministration may take the form of an aqueous or nonaqueous solution,dispersion, suspension or emulsion.

[0092] For oral administration, the active agent may be combined withone or more solid inactive ingredients for the preparation of tablets,capsules, pills, powders, granules or other suitable oral dosage forms.For example, the active agent may be combined with at least oneexcipient such as fillers, binders, humectants, disintegrating agents,solution retarders, absorption accelerators, wetting agents absorbentsor lubricating agents. According to one tablet embodiment, the activeagent may be combined with carboxymethylcellulose calcium, magnesiumstearate, mannitol and starch, and then formed into tablets byconventional tableting methods.

[0093] The specific dose of α,β unsaturated aryl sulfone to obtain thecytoprotective benefit will, of course, be determined by the particularcircumstances of the individual patient including, the size, weight, ageand sex of the patient, the nature and stage of the disease, theaggressiveness of the disease, and the route of administration, and thecytotoxicity of the mitotic phase cell cycle inhibitor. For example, adaily dosage of from about 0.01 to about 150 mg/kg/day may be utilized,more preferably from about 0.05 to about 50 mg/kg/day. Higher or lowerdoses are also contemplated.

[0094] The dosage, formulation, route and schedule of administration ofthe mitotic phase cell cycle inhibitor is carried out according to theknown protocols for the drug. It should be pointed out, however, that amore aggressive form of treatment, i.e. delivery of a higher dosage, iscontemplated according to the present invention due to the protection ofthe normal cells afforded by the α,β unsaturated aryl sulfones. Thus thecytoprotective effect of the sulfone may permit the physician in somecircumstances to increase the dosage of the mitotic phase cell cycleinhibitor above levels presently recommended.

[0095] While the sulfone and the mitotic phase cell cycle inhibitor maybe administered by different routes, the same route of administration ispreferred.

[0096] The α,β unsaturated aryl sulfones may take the form orpharmaceutically acceptable salts. The term “pharmaceutically acceptablesalts”, embraces salts commonly used to form alkali metal salts and toform addition salts of free acids or free bases. The nature of the saltis not critical, provided that it is pharmaceutically-acceptable.Suitable pharmaceutically acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of suchinorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric,carbonic, sulfuric and phosphoric acid. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, exampleof which are formic, acetic, propionic, succinic, glycolic, gluconic,lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric,pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, algenic, beta-hydroxybutyric,galactaric and galacturonic acid. Suitable pharmaceutically acceptablebase addition salts include metallic salts made from calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. All ofthese salts may be prepared by conventional means from the correspondingα,β unsaturated aryl sulfone by reacting, for example, the appropriateacid or base with the sulfone compound.

[0097] The α,β unsaturated aryl sulfones are characterized by cis-transisomerism resulting from the presence of one or more double bonds. Thecompounds are named according to the Cahn-Ingold-Prelog system, theIUPAC 1974 Recommendations, Section E: Stereochemistry, in Nomenclatureof Organic Chemistry, John Wiley & Sons, Inc., New York, N.Y., 4^(th)ed., 1992, p. 127-138. Stearic relations around a double bond aredesignated as “Z” or “E”.

[0098] (E)-α,β unsaturated aryl sulfones may be prepared by Knoevenagelcondensation of aromatic aldehydes with benzylsulfonyl acetic acids orarylsulfonyl acetic acids. The procedure is described by Reddy et al.,Acta. Chim. Hung. 115:269-71 (1984); Reddy et al., Sulfur Letters13:83-90 (1991); Reddy et al., Synthesis No. 4, 322-23 (1984); and Reddyet al., Sulfur Letters 7:43-48 (1987), the entire disclosures of whichare incorporated herein by reference.

[0099] According to the Scheme 1 below, R_(a) and R_(b) each representfrom zero to five substituents on the depicted aromatic nucleus. Forpurposes of illustration, and not limitation, the aryl groups arerepresented as phenyl groups, that is, the synthesis is exemplified bythe preparation of styryl benzylsulfones. Accordingly, the benzylthioacetic acid B is formed by the reaction of sodium thioglycollate anda benzyl chloride A. The benzyl thioacetic acid B is then oxidized with30% hydrogen peroxide to give a corresponding benzylsulfonyl acetic acidC. Condensation of the benzylsulfonyl acetic acid C with an aromaticaldehyde D via a Knoevenagel reaction in the presence of benzylamine andglacial acetic acid yields the desired (E)-styryl benzylsulfone E.

[0100] The following is a more detailed two-part synthesis procedure forpreparing (E)-styryl benzylsulfones according to the above scheme.

General Procedure 1 Synthesis (E)-Styryl Benzylsulfones

[0101] Part A. To a solution of (8 g, 0.2 mol) sodium hydroxide inmethanol (200 ml), thioglycollic acid (0.1 mol) is added slowly and theprecipitate formed is dissolved by stirring the contents of the flask.Then an appropriately substituted benzyl chloride (0.1 mol) is addedstepwise and the reaction mixture is refluxed for 2-3 hours. The cooledcontents are poured onto crushed ice and neutralized with dilutehydrochloric acid (200 ml). The resulting corresponding benzylthioaceticacid (0.1 mol) is subjected to oxidation with 30% hydrogen peroxide(0.12 mol) in glacial acetic acid (125 ml) by refluxing for 1 hour. Thecontents are cooled and poured onto crushed ice. The separated solid isrecrystallized from hot water to give the corresponding purebenzylsulfonylacetic acid.

[0102] Part B. A mixture of the benzylsulfonyl acetic acid (10 mmol), anappropriately substituted aromatic aldehyde (10 mmol), and benzylamine(200 ml) in glacial acetic acid (12 ml) is refluxed for 2-3 hours. Thecontents are cooled and treated with cold ether (50 ml). Any productprecipitated out is separated by filtration. The filtrate is dilutedwith more ether and washed successively with a saturated solution ofsodium bicarbonate (20 ml), sodium bisulfite (20 ml), dilutehydrochloric acid (20 ml) and finally with water (35 ml). Evaporation ofthe dried ethereal layer yields styryl benzylsulfones as a solidmaterial.

[0103] According to an alternative to Part A, the appropriatebenzylsulfonylacetic acids may be generated by substituting athioglycollate HSCH₂COOR for thioglycollic acid, where R is an alkylgroup, typically C1-C6 alkyl. This leads to the formation of thealkylbenzylthioacetate intermediate (F),

[0104] which is then converted to the corresponding benzyl thioaceticacid B by alkaline or acid hydrolysis.

[0105] (E)-styryl phenyl sulfones (formula I: n=zero; Q₁, Q₂=substitutedor unsubstituted phenyl) are prepared according to the method of GeneralProcedure 1, replacing the benzylsulfonyl acetic acid in Part B with theappropriate substituted or unsubstituted phenylsulfonyl acetic acid.

[0106] (Z)-Styryl benzylsulfones are prepared by the nucleophilicaddition of the appropriate thiols to substituted phenylacetylene withsubsequent oxidation of the resulting sulfide by hydrogen peroxide toyield the (Z)-styryl benzylsulfone. The procedure is generally describedby Reddy et al., Sulfur Letters 13:83-90 (1991), the entire disclosureof which is incorporated herein as a reference.

[0107] In the first step of the (Z)-styryl benzylsulfones synthesis, thesodium salt of benzyl mercaptan or the appropriate substituted benzylmercaptan is allowed to react with phenylacetylene or the appropriatesubstituted phenylacetylene forming the pure (Z)-isomer of thecorresponding styryl benzylsulfide in good yield.

[0108] In the second step of the synthesis, the (Z)-styryl benzylsulfideintermediate is oxidized to the corresponding sulfone in the pure(Z)-isomeric form by treatment with hydrogen peroxide.

[0109] The following is a more detailed two-part synthesis procedure forpreparing (Z)-styryl benzylsulfones:

Procedure 2 Synthesis of (Z)-Styryl Benzylsulfones

[0110] Part A. To a refluxing methanolic solution of substituted orunsubstituted sodium benzylthiolate prepared from 460 mg (0.02 g atom)of (i) sodium, (ii) substituted or unsubstituted benzyl mercaptan (0.02mol) and (iii) 80 ml of absolute methanol, is added freshly distilledsubstituted or unsubstituted phenylacetylene. The mixture is refluxedfor 20 hours, cooled and then poured on crushed ice. The crude productis filtered, dried and recrystallized from methanol or aqueous methanolto yield a pure (Z)-styryl benzylsulfide.

[0111] Part B. An ice cold solution of the (Z)-styryl benzylsulfide (3.0g) in 30 ml of glacial acetic acid is treated with 7.5 ml of 30%hydrogen peroxide. The reaction mixture is refluxed for 1 hour and thenpoured on crushed ice. The separated solid is filtered, dried, andrecrystallized from 2-propanol to yield the pure (Z)-styrylbenzylsulfone. The purity of the compounds is ascertained by thin layerchromatography and geometrical configuration is assigned by analysis ofinfrared and nuclear magnetic resonance spectral data.

[0112] The bis(styryl) sulfones of formula VI are prepared according toProcedure 3:

Procedure 3 Synthesis of (E)(E)- and (E)(Z)-bis(Styryl) Sulfones

[0113] To freshly distilled phenyl acetylene (51.07 g, 0.5 mol) is addedsodium thioglycollate prepared from thioglycollic acid (46 g, 0.5 mol)and sodium hydroxide (40 g, 1 mol) in methanol (250 ml). The mixture isrefluxed for 24 hours and poured onto crushed ice (500 ml) aftercooling. The styrylthioacetic acid, formed after neutralization withdilute hydrochloric acid (250 ml), is filtered and dried; yield 88 g(90%); m.p. 84-86° C.

[0114] The styrylthioacetic acid is then oxidized tostyrylsulfonylacetic acid as follows. A mixture of styrylthioacetic acid(5 g, 25 mmol) in glacial acetic acid (35 ml) and 30% hydrogen peroxide(15 ml) is heated under reflux for 60 minutes and the mixture is pouredonto crushed ice (200 ml) after cooling. The compound separated isfiltered and recrystallized from hot water to give white crystallineflakes of (Z)-styrylsulfonylacetic acid; yield 2.4 g (41%); m.p. 150-51°C.

[0115] A solution of (Z)-styrylsulfonylacetic acid (2.263 g, 10 m mol)in glacial acetic acid (6 ml) is mixed with an aromatic aldehyde (10mmol) and benzylamine (0.2 ml) and refluxed for 3 hours. The reactionmixture is cooled, treated with dry ether (50 ml), and any productseparated is collected by filtration. The filtrate is diluted with moreether and washed successively with a saturated solution of sodiumhydrogen carbonate (15 ml), sodium bisulfite (15 ml), dilutehydrochloric acid (20 ml) and finally with water (30 ml). Evaporation ofthe dried ethereal layer yields (E)(Z)-bis(styryl)sulfones.

[0116] (E),(E)-bis(styryl)sulfones are prepared following the sameprocedure as described above with exception that sulfonyldiacetic acidis used in place of (Z)-styrylsulfonylacetic acid, and twice the amountof aromatic aldehyde (20 mmol) is used.

[0117] The styryl sulfones of formula VII, which are systematicallyidentified as 2-(phenylsulfonyl)-1-phenyl-3-phenyl-2-propen-1-ones, maybe prepared according to either Method A or Method B of Procedure 4:

Procedure 4 Synthesis of2-(Phenylsulfonyl)-1-phenyl-3-phenyl-2-propen-1-ones

[0118] These compounds are synthesized by two methods which employdifferent reaction conditions, solvents and catalysts.

[0119] Method A: Phenacyl aryl sulfones are made by refluxingα-bromoacetophenones (0.05 mol) and sodium arylsulfinates (0.05 mol) inabsolute ethanol (200 ml) for 6-8 hours. The product which separates oncooling is filtered and washed several times with water to remove sodiumbromide. The product is then recrystallized from ethanol:phenacyl-phenyl sulfone, m.p. 90-91° C.; phenacyl-p-fluorophenylsulfone, m.p. 148-149° C.; phenacyl-p-bromophenyl sulfone, m.p. 121-122°C.; phenacyl-p-methoxyphenyl sulfone, m.p. 104-105° C.;p-nitrophenacyl-phenyl sulfone, m.p. 136-137° C.

[0120] A solution of phenacyl aryl sulfone (0.01 mol) in acetic acid (10ml) is mixed with an araldehyde (0.01 mol) and benzylamine (0.02 ml) andrefluxed for 3 hours. The solution is cooled and dry ether (50 ml) isadded. The ethereal solution is washed successively with dilutehydrochloric acid, aqueous 10% NaOH, saturated NaHSO₃ solution andwater. Evaporation of the dried ethereal layer gives a solid productwhich is purified by recrystallization.

[0121] Method B: Dry tetrahydrofuran (200 ml) is taken in a 500 mlconical flask flushed with nitrogen. To this, a solution of titanium(IV) chloride (11 ml, 0.01 mol) in absolute carbon tetrachloride isadded dropwise with continuous stirring. The contents of the flask aremaintained at −20° C. throughout the course of the addition. A mixtureof phenacyl aryl sulfone (0.01 mol) and aromatic aldehyde (0.01 mol) isadded to the reaction mixture and pyridine (4 ml, 0.04 mol) intetrahydrofuran (8 ml) is added slowly over a period of 1 hour. Thecontents are stirred for 10-12 hours, treated with water (50 ml) andthen ether (50 ml) is added. The ethereal layer is separated and washedwith 15 ml of saturated solutions of 10% sodium hydroxide, sodiumbisulfite and brine. The evaporation of the dried ethereal layer yields2-(phenylsulfonyl)-1-phenyl-3-phenyl-2 propen-1-ones.

[0122] The practice of the invention is illustrated by the followingnon-limiting examples. The synthesis of various α,β unsaturated arylsulfone active agents, for use as cytoprotective agents according to thepractice of the invention, is set forth as “Synthesis Examples”. Othermaterial is contained in “Examples”.

Synthesis Example 1 (E)-Styryl Phenyl Sulfone

[0123] A solution of phenyl sulfonylacetic acid (0.01 mol) andbenzaldehyde (0.01 mol) was subjected to the Procedure 1, Part B. Thetitle compound was obtained in 68-72% yield.

Synthesis Example 2 (E)-4-Chlorostyryl Phenyl Sulfone

[0124] A solution of phenyl sulfonylacetic acid (0.01 mol) and4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B.The title compound was obtained in 78-80% yield.

Synthesis Example 3 (E)-2,4-Dichlorostyryl Phenyl Sulfone

[0125] A solution of phenyl sulfonylacetic acid (0.01 mol) and2,4-dichlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, PartB. The title compound was obtained in 60-65% yield.

Synthesis Example 4 (E)-4-Bromostyryl Phenyl Sulfone

[0126] A solution of phenyl sulfonylacetic acid (0.01 mol) and4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. Thetitle compound was obtained in 78-80% yield.

Synthesis Example 5 (E)-4-Chlorostyryl 4-Chlorophenyl Sulfone

[0127] A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B.The title compound was obtained in 70-72% yield.

Synthesis Example 6 (E)-4-Methylstyryl 4-Chlorophenyl Sulfone

[0128] A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and4-methylbenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B.The title compound was obtained in 60-64% yield.

Synthesis Example 7 (E)-4-Methoxystyryl 4-Chlorophenyl Sulfone

[0129] A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and4-methoxybenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B.The title compound was obtained in 68-70% yield.

Synthesis Example 8 (E)-4-Bromostyryl 4-Chlorophenyl Sulfone

[0130] A solution of 4-chlorophenyl sulfonylacetic acid (0.01 mol) and4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. Thetitle compound was obtained in 80% yield.

Synthesis Example 9 (E)-2-Chlorostyryl Benzyl Sulfone

[0131] A solution of benzyl sulfonylacetic acid (0.01 mol) and2-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B.The title compound was obtained in 72% yield.

Synthesis Example 10 E-4-Chlorostyryl Benzyl Sulfone

[0132] A solution of benzyl sulfonylacetic acid (0.01 mol) and4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B.The title compound was obtained in 78% yield.

Synthesis Example 11 E-4-Fluorostyryl 4-Chlorobenzyl Sulfone

[0133] A solution of 4-chlorobenzyl sulfonylacetic acid (0.01 mol) and4-fluorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B.The title compound was obtained in 72% yield.

Synthesis Example 12 (E)-4-Chlorostyryl 4-Chlorobenzyl Sulfone

[0134] A solution of 4-chlorobenzyl sulfonylacetic acid (0.01 mol) and4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B.The title compound was obtained in 80% yield.

Synthesis Example 13 (E)-4-Fluorostyryl 4-Fluorobenzyl Sulfone

[0135] A solution of 4-fluorobenzyl sulfonylacetic acid (0.01 mol) and4-fluorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B.The title compound was obtained in 73% yield.

Synthesis Example 14 (E)-2,4-Difluorostyryl 4-Fluorobenzyl Sulfone

[0136] A solution of 4-fluorobenzyl sulfonylacetic acid (0.01 mol) and2,4-difluorobenzaldehyde (0.01 mol) was subjected to Procedure 1, PartB. The title compound was obtained in 68% yield.

Synthesis Example 15 (E)-4-Fluorostyryl 4-Bromobenzyl Sulfone

[0137] A solution of 4-bromobenzyl sulfonylacetic acid (0.01 mol) and4-fluorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B.The title compound was obtained in 82% yield.

Synthesis Example 16 (E)-4-Bromostyryl 4-Bromobenzyl Sulfone

[0138] A solution of 4-bromobenzyl sulfonylacetic acid (0.01 mol) and4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. Thetitle compound was obtained in 88% yield.

Synthesis Example 17 (E)-4-Bromostyryl 4-Fluorobenzyl Sulfone

[0139] A solution of 4-fluorobenzyl sulfonylacetic acid (0.01 mol) and4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. Thetitle compound was obtained in 82% yield.

Synthesis Example 18 (E)-4-Chlorostyryl 4-Bromobenzyl Sulfone

[0140] A solution of 4-bromobenzylsulfonyl acetic acid (0.01 mol) and4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B.The title compound was obtained in 88% yield.

Synthesis Example 19 (E)-4-Bromostyryl 4-Chlorobenzyl Sulfone

[0141] A solution of 4-chlorobenzylsulfonyl acetic acid (0.01 mol) and4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. Thetitle compound was obtained in 92% yield.

[0142] Infrared and nuclear magnetic resonance spectroscopy analyses ofthe compounds of Synthesis Examples 1 through 19 are set forth in Table1: TABLE 1 IR and NMR Spectroscopy IR (KR pellet) Syn. Ex. vC = C vSO₂NMR (CDCl₃) (δ ppm) 1 1638 1380, 1140 6.81(1H, d, J_(H,H) = 15.6),7.2-7.8(m, 10H), 7.49(1H, d) 2 1627 1368, 1155 6.88(1H, d, J_(H,H) =15.2), 7.15-7.9(m, 9h), 7.54(1H, d) 3 1635 1370, 1140 6.92(1H, d,J_(H,H) = 15.6), 7.3-7.85(m, 9H), 7.62(1H, d) 4 1642 1355, 1142 6.90(1H,d, J_(H,H) = 15.4), 7.25-7.9(m, 9H), 7.58(1H, d) 5 1645 1328, 11266.86(1H, d, J_(H,H) = 15.6), 7.30-7.75(m, 8H), 7.55(1H, d) 6 1650 1344,1116 2.45(3H, s), 6.83(1H, d, J_(H,H) = 15.8), 7.25-7.85(m, 8H),7.48(1H, d) 7 1658 1320, 1128 3.85(3H, s), 6.85(1H, d, J_(H,H) = 15.4),7.28-7.82(m, 8H), 7.60(1H, d) 8 1660 1311, 1148 6.84(1H, d, J_(H,H) =15.6), 7.25-7.8(m, 8H), 7.60(1H, d) 9 1638 1318, 1140 4.30(2H, s),6.81(1H, d, J_(H,H) = 15.6), 7.30-7.75(m, 9H), 7.58(1H) 10 1642 1312,1140 4.34(2H, s), 6.78(1H, d, J_(H,H) = 15.7), 7.26-7.85(m, 9H),7.54(1H) 11 1650 1305, 1150 4.32(2H, s), 6.82(1H, d, J_(H,H) = 16.0),7.22-7.76(m, 8H), 7.52(1H) 12 1658 1316, 1132 4.38(2H, s) 6.86(1H, d,J_(H,H) = 16.2), 7.26-7.85(m, 8H), 7.58(1H) 13 1640 1307, 1132 4.44(2H,s), 6.84(1H, d, J_(H,H) = 15.8), 7.20-7.78(m, 8H), 7.58(1H) 14 16461326, 1145 4.40(2H, s), 6.88(1H, d, J_(H,H) = 15.6), 7.33-7.72(m, 7H),7.58(1H) 15 1660 1330, 1144 4.46(2H, s), 6.90(1H, d, J_(H,H) = 16.2),7.24-7.78(m, 8H), 7.58(1H) 16 1658 1316, 1132 4.38(2H, s), 6.76(1H, d,J_(H,H) = 16.3), 7.36-7.84(m, 8H), 7.58(1H) 17 1644 1314, 1152 4.43(2H,s), 6.84(1H, d, J_(H,H) = 15.8), 7.28-7.76(m, 8H), 7.60(1H) 18 16521321, 1148 4.42(2H, s), 6.78(1H, d, J_(H,H) = 16.0), 7.34-7.80(m, 8H),7.54(1H) 19 1638 1330, 1138 4.38(2H, s), 6.82(1H, d, J_(H,H) = 15.6),7.28-7.78(m, 8H), 7.55(1H)

Synthesis Example 20 (E)-4-Fluorostyryl-4-Trifluoromethylbenzylsulfone

[0143] A solution of 4-trifluoromethylbenzylsulfonylacetic acid (10mmol) and 4-fluorobenzaldehyde (10 mmol) was subjected to the Procedure1, Part B. The title compound melting point 166-168° C., was obtained in82% yield.

Synthesis Example 21 (E)-4-Chlorostyryl-4-Trifluoromethylbenzylsulfone

[0144] A solution of 4-trifluoromethylbenzylsulfonylacetic acid (10mmol) and 4-chlorobenzaldehyde (10 mmol) was subjected to the Procedure1, Part B. The title compound, melting point 164-168° C., was obtainedin 88% yield.

Synthesis Example 22 (E)-4-Bromostyryl-4-Trifluoromethylbenzylsulfone

[0145] A solution of 4-trifluoromethylbenzylsulfonylacetic acid (10mmol) and 4-bromobenzaldehyde (10 mmol) was subjected to the Procedure1, Part B. The title compound, melting point 181-183° C., was obtainedin 85% yield.

Synthesis Example 23 (E)-4-Fluorostyryl-2,4-dichlorobenzylsulfone

[0146] A solution of 2,4-dichlorobenzylsulfonyl acid (10 mmol) and4-fluorobenzaldehyde (10 mmol) was subjected to the Procedure 1, Part B.The title compound, melting point 146-148° C., was obtained in 78%yield.

Synthesis Example 24 (E)-4-Chlorostyryl-2,4-Dichlorobenzylsulfone

[0147] A solution of 2,4-dichlorobenzylsulfonylacetic acid (10 mmol) and4-chlorobenzaldehyde (10 mmol) was subjected to the Procedure 1, Part B.The title compound, melting point 148-149° C., was obtained in 84%yield.

Synthesis Example 25 (E)-4-Fluorostyryl-3,4-Dichlorobenzylsulfone

[0148] A solution of 3,4-dichlorobenzylsulfonylacetic acid (10 mmol) and4-fluorobenzaldehyde (10 mmol) was subjected to the Procedure 1, Part B.The title compound, melting point 120-122° C., was obtained in 82%yield.

Synthesis Example 26 (E)-4-Chlorostyryl-3,4-Dichlorobenzylsulfone

[0149] A solution of 3,4-dichlorobenzylsulfonylacetic acid (10 mmol) and4-chlorobenzaldehyde (10 mmol) was subjected to the Procedure 1, Part B.The title compound, melting point 149-151° C., was obtained in 86%yield.

Synthesis Example 27 (E)-4-Bromostyryl-3,4-Dichlorobenzylsulfone

[0150] A solution of 3,4-dichlorobenzylsulfonylacetic acid (10 mmol) and4-bromobenzaldehyde (10 mmol) was subjected to the Procedure 1, Part B.The title compound, melting point 154-155° C., was obtained in 84%yield.

Synthesis Example 28 (E)-4-Bromostyryl-4-Nitrobenzylsulfone

[0151] A solution of 4-nitrobenzylsulfonylacetic acid (10 mmol) and4-bromobenzaldehyde (10 mmol) was subjected to the Procedure 1, Part B.The title compound, melting point 160-161° C., was obtained in 76%yield.

Synthesis Example 29 (E)-4-Fluorostyryl-4-Cyanobenzylsulfone

[0152] A solution of 4-cyanobenzylsulfonylacetic acid (10 mmol) and4-fluorobenzaldehyde (10 mmol) was subjected to the Procedure 1 Part B.The title compound, melting point 150-151° C., was obtained in 82%yield.

Synthesis Example 30 (E)-4-Chlorostyryl-4-Cyanobenzylsulfone

[0153] A solution of 4-cyanobenzylsulfonyl acetic acid (10 mmol) and4-chlorobenzaldehyde (10 mmol) was subjected to the Procedure 1, Part B.The title compound, melting point 173-177° C., was obtained in 86%yield.

Synthesis Example 31 (E)-4-Bromostyryl-4-Cyanobenzylsulfone

[0154] A solution of 4-cyanobenzylsulfonyl acetic acid (10 mmol) and4-bromobenzaldehyde (10 mmol) was subjected to the Procedure 1, Part B.The title compound, melting point 183-184° C., was obtained in 77%yield.

Synthesis Example 32 (E)-3,4-Difluorostyryl-4-Chlorobenzylsulfone

[0155] A solution of 4-chlorobenzylsulfonyl acetic acid (10 mmol) and3,4 difluorobenzaldehyde was subjected to the Procedure 1, Part B. Thetitle compound, melting point 204-205° C., was obtained in 73% yield.

Synthesis Example 33 (E)-3-Chloro-4-Fluorostyryl-4-Chlorobenzylsulfone

[0156] A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and3-chloro-4-fluorobenzaldehyde was subjected to the Procedure 1, Part B.The title compound, melting point 181-183° C., was obtained in 78%yield.

Synthesis Example 34 (E)-2-Chloro-4-Fluorostyryl-4-Chlorobenzylsulfone

[0157] A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and2-chloro-4-fluorobenzaldehyde was subjected to the Procedure 1, Part B.The title compound, melting point 149-150° C., was obtained in 68%yield.

Synthesis Example 35 (E)-2,4-Dichlorostyryl-4-Chlorobenzylsulfone

[0158] A solution of 4-chlorobenzylsulfonylacetic acid (10 mmol) and2,4-dichlorobenzaldehyde was subjected to the Procedure 1, Part B. Thetitle compound, melting point 164-165° C., was obtained in 78% yield.

Synthesis Example 36 (E)-3,4-Dichlorostyryl-4-Chlorobenzylsulfone

[0159] A solution of 4-chlorobenzylsulfonyl acetic acid (10 mmol) and3,4 dichlorobenzaldehyde (10 mmol) was subjected to the Procedure 1,Part B. The title compound, melting point 170-171° C., was obtained in73% yield.

Synthesis Example 37 (E)-2,3-Dichlorostyryl-4-Chlorobenzylsulfone

[0160] A solution of 4-chlorobenzylsulfonyl acetic acid (10 mmol) and2,3-dichlorobenzaldehyde (10 mmol was subjected to the Procedure 1, partB. The title compound, melting point 170-171° C., was obtained in 72%yield.

Synthesis Example 38 (Z)-Styryl Benzylsulfone

[0161] A solution of phenylacetylene (0.02 mol) and benzyl mercaptan(0.02 mol) and metallic sodium (0.02 g atom) was subjected to theProcedure 2, part A, to form (Z)-styryl benzylsulfide. The titlecompound was obtained in 65% yield by oxidation of the sulfide accordingto the Procedure 2, part B. ¹HNMR (CDCl₃) δ4.50 (2H, s), 6.65 (1H, d,J_(H,H)=11.2), 7.18-7.74 (10H aromatic+1H ethylenic).

Synthesis Example 39 (Z)-Styryl 4-Chlorobenzylsulfone

[0162] A solution of phenylacetylene (0.02 mol) and 4-chlorobenzylmercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected toProcedure 2 to form (Z)-styryl 4-chlorobenzylsulfide. The title compoundwas obtained in 72% yield following oxidation. ¹HNMR (CDCl₃) δ4.56 (2H,s), 6.68 (1H, d, J_(H,H)=11.8), 7.20-7.64 (9H aromatic+1H ethylenic).

Synthesis Example 40 (Z)-Styryl 2-Chlorobenzylsulfone

[0163] A solution of phenylacetylene (0.02 mol) and 2-chlorobenzylmercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected toProcedure 2 to form (Z)-styryl 2-chlorobenzylsulfide. The title compoundwas obtained in 68% yield following oxidation. ¹HNMR (CDCl₃) δ4.50 (2H,s), 6.65 (1H, d, J_(H,H)=12.0), 7.18-7.74 (9H aromatic+1H ethylenic).

Synthesis Example 41 (Z)-Styryl 4-Fluorobenzylsulfone

[0164] A solution of phenylacetylene (0.02 mol) and 4-fluorobenzylmercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected toProcedure 2 to from (Z)-styryl 4-fluorobenzylsulfide. The title compoundwas obtained in 70% yield following oxidation. ¹HNMR (CDCl₃) δ4.58 (2H,s), 6.62 (1H, d, J_(H,H)=11.86), 7.18-7.60 (9H aromatic+1H ethylenic).

Synthesis Example 42 (Z)-4-Chlorostyryl Benzylsulfone

[0165] A solution of 4-chlorophenylacetylene (0.02 mol) and benzylmercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected toProcedure 2 to form (Z)-4-chlorostyryl benzylsulfide. The title compoundwas obtained in 74% yield following oxidation. ¹HNMR (CDCl₃) δ4.55 (2H,s), 6.66 (1H, d, J_(H,H)=12.12), 7.16-7.65 (9H aromatic+1H ethylenic).

Synthesis Example 43 (Z)-4-Chlorostyryl 4-Chlorobenzylsulfone

[0166] A solution of 4-chlorophenylacetylene (0.02 mol) and4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom)was subjected to Procedure 2 to form (Z)-4-chlorostyryl4-chlorobenzylsulfide. The title compound was obtained in 76% yieldfollowing oxidation. ¹HNMR (CDCl₃) δ4.62 (2H, s), 6.68 (1H, d,J_(H,H)=11.92), 7.18-7.60 (8H aromatic+1H ethylenic).

Synthesis Example 44 (Z)-4-Chlorostyryl 2-Chlorobenzylsulfone

[0167] A solution of 4-chlorophenylacetylene (0.02 mol) and2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom)was subjected to Procedure 2 to form (Z)-4-chlorostyryl2-chlorobenzylsulfide. The title compound was obtained in 73% yieldfollowing oxidation. ¹HNMR (CDCl₃) δ4.56 (2H, s), 6.70 (1H, d,J_(HH)=12.05), 7.18-7.64 (8H aromatic+1H ethylenic).

Synthesis Example 45 (Z)-4-Chlorostyryl 4-Fluorobenzylsulfone

[0168] A solution of 4-chlorophenylacetylene (0.02 mol) and4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom)was subjected to Procedure 2 to form (Z)-4-chlorostyryl4-fluorobenzylsulfide. The title compound was obtained in 82% yieldfollowing oxidation. ¹HNMR (CDCl₃) δ4.60 (2H, s), 6.70 (1H, d,J_(H,H)=11.78), 7.18-7.60 (8H aromatic+1H ethylenic).

Synthesis Example 46 (Z)-4-Fluorostyryl Benzylsulfone

[0169] A solution of 4-fluorophenylacetylene (0.02 mol) and benzylmercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected toProcedure 2 to form (Z)-4-fluorostyryl benzylsulfide. The title compoundwas obtained in 76% yield following oxidation. ¹HNMR (CDCl₃) δ4.54 (2H,s), 6.68 (1H, d, J_(H,H)=11.94), 7.12-7.58 (9H aromatic+1H ethylenic).

Synthesis Example 47 (Z)-4-Fluorostyryl 4-Chlorobenzylsulfone

[0170] A solution of 4-fluorophenylacetylene (0.02 mol) and4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom)was subjected to Procedure 2 to form (Z)-4-fluorostyryl4-chlorobenzylsulfide. The title compound was obtained in 82% yieldfollowing oxidation. ¹HNMR (CDCl₃) δ4.60 (2H, s), 6.68 (1H, d,J_(H,H)=11.84), 7.18-7.60 (8H aromatic+1H ethylenic).

Synthesis Example 48 (Z)-4-Fluorostyryl 2-Chlorobenzylsulfone

[0171] A solution of 4-fluorophenylacetylene (0.02 mol) and2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom)was subjected to Procedure 2 to form (Z)-4-fluorostyryl2-chlorobenzylsulfide. The title compound was obtained in 74% yieldfollowing oxidation. ¹HNMR (CDCl₃) δ4.55 (2H, s), 6.66 (1H, d,J_(HH)=11.94), 7.20-7.65 (8H aromatic+1H ethylenic).

Synthesis Example 49 (Z)-4-Fluorostyryl 4-Fluorobenzylsulfone

[0172] A solution of 4-fluorophenylacetylene (0.02 mol) and4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom)was subjected to Procedure 2 to form (Z)-4-fluorostyryl4-fluorobenzylsulfide. The title compound was obtained in 78% yieldfollowing oxidation. ¹HNMR (CDCl₃) δ4.60 (2H, s), 6.65 (1H, d,J_(H,H)=11.83), 7.20-7.65 (8H aromatic+1H ethylenic).

Synthesis Example 50 (Z)-4-Bromostyryl Benzylsulfone

[0173] A solution of 4-bromophenylacetylene (0.02 mol) and benzylmercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected toProcedure 2 to form (Z)-4-bromostyryl benzylsulfide. The title compoundwas obtained in 80% yield following oxidation. ¹HNMR (CDCl₃) δ4.52 (2H,s), 6.80 (1H, d, J_(H,H)=11.98), 7.18-7.59 (9H aromatic+1H ethylenic).

Synthesis Example 51 (Z)-4-Bromostyryl 4-Chlorobenzylsulfone

[0174] A solution of 4-bromophenylacetylene (0.02 mol) and4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom)was subjected to Procedure 2 to form (Z)-4-bromostyryl4-chlorobenzylsulfide. The title compound was obtained in 87% yieldfollowing oxidation. ¹HNMR (CDCl₃) δ4.58 (2H, s), 6.72 (1H, d,J_(HH)=12.08), 7.15-7.68 (8H aromatic+1H ethylenic).

Synthesis Example 52 (Z)-4-Bromostyryl 2-Chlorobenzylsulfone

[0175] A solution of 4-bromophenylacetylene (0.02 mol) and2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom)was subjected to Procedure 2 to form (Z)-4-bromostyryl2-chlorobenzylsulfide. The title compound was obtained in 84% yieldfollowing oxidation. ¹HNMR (CDCl₃) δ4.57 (2H, s), 6.70 (1H, d,J_(H,H)=11.58), 7.18-7.58 (8H aromatic+1H ethylenic).

Synthesis Example 53 (Z)-4-Bromostyryl 4-Fluorobenzylsulfone

[0176] A solution of 4-bromophenylacetylene (0.02 mol) and4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom)was subjected to Procedure 2 to from (Z)-4-bromostyryl4-fluorobenzylsulfide. The title compound was obtained in 78% yieldfollowing oxidation. ¹HNMR (CDCl₃) δ4.58 (2H, s), 6.65 (1H, d,J_(H,H)=11.78), 7.22-7.67 (8H aromatic+1H ethylenic).

Synthesis Example 54 (Z)-4-Methylstyryl Benzylsulfone

[0177] A solution of 4-methylphenylacetylene (0.02 mol) and benzylmercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected toProcedure 2 to form (Z)-4-methylstyryl benzylsulfide. The title compoundwas obtained in 70% yield following oxidation. ¹HNMR (CDCl₃) δ2.48 (3H,s), 4.60 (2H, s), 6.68 (1H, d, J_(H,H)=11.94), 7.20-7.65 (9H aromatic+1Hethylenic).

Synthesis Example 55 (Z)-4-Methylstyryl 4-Chlorobenzylsulfone

[0178] A solution of 4-methylphenylacetylene (0.02 mol) and4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom)was subjected to Procedure 2 to form (Z)-4-methylstyryl4-chlorobenzylsulfide. The title compound was obtained in 74% yieldfollowing oxidation. ¹HNMR (CDCl₃) δ2.46 (3H, s), 4.64 (2H, s), 6.75(1H, d, J_(H,H)=12.21), 7.18-7.57 (9H aromatic+1H ethylenic).

Synthesis Example 56 (Z)-4-Methylstyryl 2-Chlorobenzylsulfone

[0179] A solution of 4-methylphenylacetylene (0.02 mol) and2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom)was subjected to Procedure 2 to form (Z)-4-methylstyryl2-chlorobenzylsulfide. The title compound was obtained in 76% yieldfollowing oxidation. ¹HNMR (CDCl₃) δ2.50 (3H, s), 4.58 (2H, s), 6.80(1H, d, J_(H,H)=11.88), 7.20-7.63 (9H aromatic+1H ethylenic).

Synthesis Example 57 (Z)-4-Methylstyryl 4-Fluorobenzylsulfone

[0180] A solution of 4-methylphenylacetylene (0.02 mol) and4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom)was subjected to Procedure 2 to form (Z)-4-methylstyryl4-fluorobenzylsulfide. The title compound was obtained in 69% yieldfollowing oxidation. ¹HNMR (CDCl₃) δ2.46 (3H, s), 4.62 (2H, s), 6.78(1H, d, J_(H,H)=11.98), 7.18-7.59 (9H aromatic+1H ethylenic)

[0181] The following additional (E)-α,β unsaturated aryl sulfones listedin Tables 3a and 3b were prepared by reacting the appropriatebenzylsulfonyl acetic acid and benzaldehyde or arylaldehyde according toProcedure 1, Part B: TABLE 3a Syn. Yield Ex. M.P. (° C.) (%) Compound 58134-136 55 (E)-2-nitrostyryl-4-fluorobenzylsulfone 59 170-173 64(E)-3-nitrostyryl-4-fluorobenzylsulfone 60 151-152 61(E)-4-nitrostyryl-4-fluorobenzylsulfone 61 96-98 54(E)-2-trifluoromethylstyryl-4-fluorobenzylsulfone 62 117-119 55(E)-3-trifluoromethylstyryl-4-fluorobenzylsulfone 63 125-128 73(E)-4-trifluoromethylstyryl-4-fluorobenzylsulfone 64 108-112 52(E)-2-trifluoromethyl-4-fluorostyryl-4-fluorobenzylsulfone 65 128-132 58(E)-2-nitrostyryl-4-chlorobenzylsulfone 66 156-157 60(E)-3-nitrostyryl-4-chlorobenzylsulfone 67 189-191 61(E)-4-nitrostyryl-4-chlorobenzylsulfone 68 100-101 55(E)-2-trifluoromethylstyryl-4-chlorobenzylsulfone 69 155-157 58(E)-3-trifluoromethylstyryl-4-chlorobenzylsulfone 70 164-166 59(E)-4-trifluoromethylstyryl-4-chlorobenzylsulfone 71 115-117 63(E)-2-trifluoromethyl-4-fluorostyryl-4-chlorobenzylsulfone 72 169-171 63(E)-3-methyl-4-fluorostyryl-4-chlorobenzylsulfone 73 136-138 57(E)-2-nitrostyryl-2,4-dichlorobenzylsulfone 74 136-138 57(E)-2-trifluoromethyl-4-fluorostyryl-2,4-dichlorobenzylsulfone 75131-132 63 (E)-2-nitrostyryl-4-bromobenzylsulfone 76 168-170 56(E)-3-nitrostyryl-4-bromobenzylsulfone 77 205-207 67(E)-4-nitrostyryl-4-bromobenzylsulfone 78 102-104 57(E)-2-trifluoromethylstyryl-4-bromobenzylsulfone 79 160-161 55(E)-3-trifluoromethylstyryl-4-fluorobenzylsulfone 80 174-175 62(E)-4-trifluoromethylstyryl-4-bromobenzylsulfone 81 167-168 63(E)-2-nitrostyryl-4-cyanobenzylsulfone 82 192-193 62(E)-3-nitrostyryl-4-cyanobenzylsulfone 83 219-220 66(E)-4-nitrostyryl-4-cyanobenzylsulfone 84 182-184 70(E)-4-fluorostyryl-4-methylbenzylsulfone 85 191-192 70(E)-4-bromostyryl-4-methylbenzylsulfone 86 128-130 51(E)-2-nitrostyryl-4-methylbenzylsulfone 87 201-203 56(E)-3-nitrostyryl-4-methylbenzylsulfone 88 194-195 57(E)-4-nitrostyryl-4-methylbenzylsulfone 89 148-149 60(E)-4-fluorostyryl-4-methoxybenzylsulfone 90 176-177 66(E)-4-chlorostyryl-4-methoxybenzylsulfone 91 179-181 60(E)-4-bromostyryl-4-methoxybenzylsulfone 92 127-129 57(E)-2-nitrostyryl-4-methoxybenzylsulfone 93 153-155 59(E)-3-nitrostyryl-4-methoxybenzylsulfone 94 179-181 56(E)-4-nitrostyryl-4-methoxybenzylsulfone 95 176-177 66(E)-4-chlorostyryl-4-nitrobenzylsulfone 96 199-200 60(E)-4-fluorostyryl-4-nitrobenzylsulfone

[0182] TABLE 3b 97 133-136 80(E)-2,3,4,5,6-pentafluorostyryl-4-fluorobenzylsulfone 98 146-148 82(E)-2,3,4,5,6-pentafluorostyryl-4-chlorobenzylsulfone 99 163-164 85(E)-2,3,4,5,6-pentafluorostyryl-4-bromobenzylsulfone 100 133-136 78(E)-4-fluorostyryl-2,3,4,5,6-pentafluorobenzylsulfone 101 154-155 80(E)-4-chlorostyryl-2,3,4,5,6-pentafluorobenzylsulfone 102 176-177 92(E)-4-bromostyryl-2,3,4,5,6-pentafluorobenzylsulfone 103 171-173 84(E)-2,3,4,5,6-pentafluorostyryl-3,4-dichlorobenzylsulfone 104 137-139 84(E)-2,3,4,5,6-pentafluorostyryl-2,3,4,5,6- pentafluorobenzylsulfone 105178-181 51 (E)-2,3,4,5,6-pentafluorostyryl-4-iodobenzylsulfone 106211-212 54 (E)-2-hydroxy-3,5-dinitrostyryl-4-fluorobenzylsulfone 107207-209 52 (E)-2-hydroxy-3,5-dinitrostyryl-4-bromobenzylsulfone 108204-205 51 (E)-2-hydroxy-3,5-dinitrostyryl-4-chlorobenzylsulfone 109212-213 56 (E)-2-hydroxy-3,5-dinitrostyryl-2,4-dichlorobenzylsulfone 110142-144 52 (E)-2,4,6-trimethoxystyryl-4-methoxybenzylsulfone 111 160-16152 (E)-3-methyl-2,4-dimethoxystyryl-4-methoxybenzylsulfone 112 138-14054 (E)-3,4,5-trimethoxystyryl-4-methoxybenzylsulfone 113 ND ND(E)-3,4,5-trimethoxystyryl-2-nitro-4,5-dimethoxybenzylsulfone 114 ND ND(E)-2,4,6-trimethoxystyryl-2-nitro-4,5-dimethoxybenzylsulfone 115 ND ND(E)-3-methyl-2,4-dimethoxystyryl-2-nitro-4,5- dimethoxybenzylsulfone 116128-129 72 (E)-2,3,4-trifluorostyryl-4-fluorobenzylsulfone 117 141-14278 (E)-2,3,4-trifluorostyryl-4-chlorobenzylsulfone 118 134-136 58(E)-2,6-dimethoxy-4-hydroxystyryl-4-methoxybenzylsulfone 119 154-156 56(E)-2,3,5,6-tetrafluorostyryl-4-methoxybenzylsulfone 120 146-148 66(E)-2,4,5-trimethoxystyryl-4-methoxybenzylsulfone 121 154-156 52(E)-2,3,4-trimethoxystyryl-4-methoxybenzylsulfone 122 203-205 56(E)-3-nitro-4-hydroxy-5-methoxystyryl-4-methoxybenzylsulfone 123 139-14154 (E)-3,4-dimethoxy-6-nitrostyryl-4-methoxybenzylsulfone 124 160-161 58(E)-3,4-dimethoxy-5-iodostyryl-4-methoxybenzylsulfone 125 146-148 55(E)-2,6-dimethoxy-4-fluorostyryl-4-methoxybenzylsulfone 126 ND ND(E)-2-hydroxy-4,6-dimethoxystyryl-4-methoxybenzylsulfone 127 97-99 51(E)-2,4,6-trimethylstyryl-4-methoxybenzylsulfone 128 181-183 54(E)-2,4,6-trimethoxystyryl-4-chlorobenzylsulfone 129 119-121 55(E)-2,6-dimethoxy-4-fluorostyryl-4-chlorobenzylsulfone 130 ND ND(E)-2-hydroxy-4,6-dimethoxystyryl-4-chlorobenzylsulfone 131 178-181 54(E)-2,4,6-trimethoxystyryl-4-bromobenzylsulfone 132 116-118 58(E)-2,6-dimethoxy-4-fluorostyryl-4-bromobenzylsulfone 133 94-96 52(E)-2,4,6-trimethoxystyryl-2,3,4-trimethoxybenzylsulfone 134 110-112 54(E)-2,6-dimethoxystyryl-2,3,4-trimethoxybenzylsulfone 135 151-153 54(E)-2,4,6-trimethoxystyryl-3,4,5-trimethoxybenzylsulfone 136 146-149 53(E)-2,6-dimethoxystyryl-3,4,5-trimethoxybenzylsulfone 137 96-99 68(E)-4-fluorostyryl-2,3,4-trimethoxybenzylsulfone

[0183] Examples of further (E)-α,β unsaturated aryl sulfone compoundsaccording to formula 1a, below, are provided in Table 4. In eachcompound, one of Q₁ or Q₂ is other than phenyl or substituted phenyl.Each compound was prepared by reacting the appropriate benzylsulfonylacetic acid or (aryl)methyl sulfonyl acetic acid with the appropriatebenzaldehyde or arylaldehyde according to Procedure 1, Part B.3-Thiophene-1,1-dioxoethenyl compounds were prepared from thecorresponding 3-thiopheneethenyl compound by refluxing a solution of the3-thiopheneethenyl compound in glacial acetic acid (10 ml) and 30%hydrogen peroxide (1 ml) for 1 hour, followed by pouring the cooledcontents onto crushed ice (100 g). The solid material separated wasfiltered and recrystallized from 2-propanol. TABLE 4 Ia

Syn. Ex. M.P.(° C.) % Yield Q₁ Q₂ 138 110-111 54 4-fluorophenyl2-pyridyl 139 155-156 60 4-fluorophenyl 3-pyridyl 140 ND 524-fluorophenyl 4-pyridyl 141 117-119 53 4-chlorophenyl 2-pyridyl 142167-169 51 4-chlorophenyl 3-pyridyl 143 107-109 53 4-chlorophenyl4-pyridyl 144 143-145 52 4-bromophenyl 2-pyridyl 145 161-162 594-bromophenyl 3-pyridyl 146 158-160 54 4-bromophenyl 4-pyridyl 147146-148 53 4-fluorophenyl 2-thienyl 149 158-159 56 4-chlorophenyl2-thienyl 149 169-170 54 4-bromophenyl 2-thienyl 150 155-157 544-fluorophenyl 4-bromo-2-thienyl 151 150-151 53 4-chlorophenyl4-bromo-2-thienyl 152 154-155 54 4-bromophenyl 4-bromo-2-thienyl 153161-162 55 4-fluorophenyl 5-bromo-2-thienyl 154 190-192 504-chlorophenyl 5-bromo-2-thienyl 155 199-200 52 4-bromophenyl5-bromo-2-thienyl 156 126-128 52 4-fluorophenyl 2-thienyl-1,1-dioxide157 108-110 55 4-chlorophenyl 2-thienyl-1,1-dioxide 158 145-147 564-bromophenyl 2-thienyl-1,1-dioxide 159 159-161 53 4-fluorophenyl3-thienyl 160 169-170 59 4-chlorophenyl 3-thienyl 161 175-177 704-bromophenyl 3-thienyl 162 177-179 52 4-iodophenyl 3-thienyl 163135-136 55 4-methylphenyl 3-thienyl 164 130-131 55 4-methoxyphenyl3-thienyl 165 201-202 52 4-trifluoro-methyl- 3-thienyl phenyl 166125-126 53 2,4-dichlorophenyl 3-thienyl 167 152-153 513,4-dichlorophenyl 3-thienyl 168 168-170 54 4-cyanophenyl 3-thienyl 169203-205 54 4-nitrophenyl 3-thienyl 170 95-99 52 4-fluorophenyl3-thienyl-1,1-dioxide 171 115-120 51 4-chlorophenyl3-thienyl-1,1-dioxide 172 152-155 50 4-bromophenyl 3-thienyl-1,1-dioxide173 92-95 54 4-methoxyphenyl 3-thienyl-1,1-dioxide 174 135-139 522,4-dichlorophenyl 3-thienyl-1,1-dioxide 175 103-105 53 4-fluorophenyl2-furyl 176 106-108 52 4-chlorophenyl 2-furyl 177 125-127 524-bromophenyl 2-furyl 178 114-117 51 4-fluorophenyl 3-furyl 179 154-15650 4-chlorophenyl 3-furyl 180 156-158 51 4-bromophenyl 3-furyl 181166-170 52 4-iodophenyl 3-furyl 182 123-126 53 4-methylphenyl 3-furyl183 117-119 51 4-methoxyphenyl 3-furyl 184 167-169 514-trifluoro-methyl- 3-furyl phenyl 185 104-106 53 2,4-dichlorophenyl3-furyl 186 131-133 52 3,4-dichlorophenyl 3-furyl 187 175-178 534-cyanophenyl 3-furyl 188 210-213 52 4-nitrophenyl 3-furyl 189 133-13751 4-chlorophenyl 2-thiazolyl 190 ND ND 4-chlorophenyl 2-pyrrolyl 191 NDND 4-bromophenyl 2-pyrrolyl 192 228-230 56 4-chlorophenyl2-nitro-4-thienyl 193 177-179 67 4-iodophenyl 2-nitro-4-thienyl 194228-230 64 2,4-dichlorophenyl 2-nitro-4-thienyl 195 170-172 564-methoxyphenyl 2-nitro-4-thienyl 196 148-150 55 4-fluorophenyl1-naphthyl 197 185-186 58 4-fluorophenyl 2-naphthyl 198 142-143 634-chlorophenyl 1-naphthyl 199 191-193 52 4-chlorophenyl 2-naphthyl 200147-149 52 4-bromophenyl 1-naphthyl 201 193-194 54 4-bromophenyl2-naphthyl 202 142-144 52 1-naphthyl 4-fluorophenyl 203 195-197 531-naphthyl 4-chlorophenyl 204 207-209 55 1-naphthyl 4-bromophenyl 205188-192 62 1-naphthyl 2-nitrophenyl 206 192-194 59 1-naphthyl3-nitrophenyl 207 252-254 61 1-naphthyl 4-nitrophenyl 208 93-95 564-fluorophenyl 9-anthryl 209 122-124 53 4-chlorophenyl 9-anthryl 210172-175 51 4-bromophenyl 9-anthryl

[0184] Synthesis Examples 211-213 exemplify the preparation of(E)(Z)-bis(styryl) sulfones. Synthesis Examples 214-219 exemplify thepreparation of 2-(phenylsulfonyl)-1-phenyl-3-phenyl-2-propen-1-ones.

Synthesis Example 211 (Z)-Styryl-(E)-4-Fluorostyryl Sulfone

[0185] A solution of (Z)-styryl sulfonylacetic acid (0.01 mol) and4-fluorobenzaldehyde (0.01 mol was subjected to Procedure 3. The titlecompound was obtained in 68% yield.

Synthesis Example 212 (Z)-Styryl-(E)-4-Bromostyryl Sulfone

[0186] A solution of (Z)-styryl sulfonylacetic acid (0.01 mol) and4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 3. The titlecompound was obtained in 70% yield.

Synthesis Example 213 (Z)-Styryl-(E)-4-Chlorostyryl Sulfone

[0187] A solution of (Z)-styryl sulfonylacetic acid (0.01 mol) and4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 3. The titlecompound was obtained in 64% yield.

Synthesis Example 2142-[(4-fluorophenyl)sulfonyl]-1-phenyl-3-(4-fluorophenyl)-2-propen-1-one

[0188] A solution of phenacyl-4-fluorophenyl sulfone (0.01 mol) and4-fluorobenzaldehyde (0.01 mol) was subjected to Method 1 of Procedure4. The title compound was obtained in 63% yield.

Synthesis Example 2152-[(2-chlorophenyl)-sulfonyl]-1-phenyl-3-(4-fluorophenyl)-2-propen-1-one

[0189] A solution of phenacyl-2-chlorophenyl sulfone (0.01 mol) and4-fluorobenzaldehyde (0.01 mol) was subjected to Method 1 of Procedure4. The title compound was obtained in 58% yield.

Synthesis Example 2162-[(2-chlorophenyl)sulfonyl]-1-phenyl-3-(4-bromophenyl)-2-propen-1-one

[0190] A solution of phenacyl-2-chlorophenyl sulfone (0.01 mol) and4-bromobenzaldehyde (0.01 mol) was subjected to Method 1 of Procedure 4.The title compound was obtained in 66% yield.

Synthesis Example 2172-[(4-chlorophenyl)sulfonyl]-1-phenyl-3-(4-bromophenyl)-2-propen-1-one

[0191] A solution of phenacyl-4-chlorophenyl sulfone (0.01 mol) and4-bromobenzaldehyde (0.01 mol) was subjected to Method 1 of Procedure 4.The title compound was obtained in 60% yield.

Synthesis Example 2182-[(2-nitrophenyl)sulfonyl]-1-phenyl-3-(4-bromophenyl)-2-propen-1-one

[0192] A solution of phenacyl-2-nitrophenyl sulfone (0.01 mol) and4-bromobenzaldehyde (0.01 mol) was subjected to Method 1 of Procedure 4.The title compound was obtained in 56% yield.

Synthesis Example 2192-(phenylsulfonyl)-1-phenyl-3-(4-fluorophenyl)-2-propen-1-one

[0193] A solution of phenacylphenyl sulfone (0.01 mol) and4-fluorobenzaldehyde (0.01 mol) was subjected to Method 1 of Procedure4. The title compound, melting point 142-143° C., was obtained in 62%yield.

[0194] Infrared and nuclear magnetic resonance spectroscopy analyses ofthe compounds of Synthesis Examples 211 through 218 are set forth inTable 5: TABLE 5 IR and NMR Spectroscopy 211 — 1300, 1120 6.55(1H, d,J_(H,H) = 10.8), 6.70(1H, d, J_(H,H) = 14.8), 7.20-7.92 (m, 9H aromatic,2H vinyl) 212 — 1318, 1128 6.68(1H, d, J_(H,H) = 11.0), 6.86(1H, d,J_(H,H) = 15.0), 7.15-7.90 (m, 9H aromatic, 2H vinyl) 213 — 1330, 11006.65(1H, d, J_(H,H) = 11.2), 6.81(1H, d, J_(H,H) = 15.4), 7.00-7.85 (m,9H aromatic, 2H vinyl) 214 1620 1320, 1145 8.04(1H, s, —C═CH)7.35-7.95(m, 13H) 215 1625 1320, 1148 8.48(1H, s, —C═CH) 7.40-8.25(m,13H) 216 1618 1315, 1140 8.05(1H, s, —C═CH) 7.28-8.00(m, 13H) 217 16201318, 1142 8.47(1H, s, —C═CH) 7.30-8.15(m, 13H) 218 1618 1315, 11408.57(1H, s, —C═CH) 7.40-8.20(m, 13H)

Example 1 Plating Efficiency of Normal vs. Cancer Cells in the Presenceof (E)-4-Fluorostyryl-4-Chlorobenzylsulfone

[0195] HFL-1 cells (normal, human diploid lung fibroblasts) purchasedfrom ATCC were plated after first passage at low density (2.0×10⁵ cells)per well (6 well dishes) in one ml of growth medium (DMEM completed with10% fetal bovine serum and pen/strep). Twenty-four hours later,(E)-4-fluorostyryl-4-chlorobenzylsulfone was added to each well at thefollowing final concentrations; 0 μM, 2.5. μM, 5.0 μM, 25 μM, 50 μM, and75 μM. After a 24 hour incubation period, the wells were washed 3× with5 ml normal growth medium and each well was trypsinized and cell countswere determined. To determine colony-forming ability, the cells fromeach treatment were then serial diluted and replated into 100 mm dishessuch that each group was split into 3 replating groups consisting of 10,100, 200 cells per plate. The groups were plated in triplicate. Thecells were incubated for 20 days under normal growth conditions andcolonies were counted after staining with modified Wright stain (Sigma).The number of colonies from each plate in triplicate were determined andthe average for each group was plotted. The results are set forth inFIG. 1. The concentration of the drug causing 50% inhibition in platingefficiency was calculated and found to be 70 μM.

Example 2 Effect of Long Term Exposure of Normal Human Fibroblasts to(E)-4-Fluorostyryl-4-Chlorobenzylsulfone

[0196] HFL-1 cells were plated at a cell density of 1.0×10⁵ per well 24hours prior to drug addition. Cells were exposed to either 2.5 or 5.0 μM(E)-4-fluorostyryl-4-chlorobenzylsulfone for 48 or 72 hours. Cells werecounted 96 hours after the incubation period. The results are shown inFIG. 2. The cells exhibited transiently reduced replication rates.

Example 3 (E)-4-Fluorostyryl-4-Chlorobenzylsulfone Protection of NormalHuman Fibroblasts from Paclitaxel Cytotoxicity

[0197] HFL-1 cells were plated at a cell density of 1.0×10⁵ per well 24hours prior to drug addition. Cells were pretreated with(E)-4-fluorostyryl-4-chlorobenzylsulfone (2.0 μM) for 8 hours and thenexposed to paclitaxel (250 μM). Other cells were treated with paclitaxelalone, or both agents simultaneously. Cells were enumerated by Trypanblue exclusion using a hematocytometer 96 hours after exposure topaclitaxel. The results are shown in FIG. 3. The ordinate in FIG. 3represents the number of viable cells following treatment with(E)-4-fluorostyryl-4-chlorobenzylsulfone and paclitaxel, divided by thenumber of viable cells remaining after treatment with paclitaxel alone.Pretreatment with (E)-4-fluorostyryl-4-chlorobenzylsulfone conferredprotection from the toxic effects of paclitaxel.

Example 4 (E)-4-Fluorostyryl-4-Chlorobenzylsulfone Protection of NormalHuman Fibroblasts from Anticancer Agent Cytotoxicity

[0198] HFL-1 cells were plated at a cell density of 1.0×10⁵ in 1 ml ofmedium. Twenty-four hours following plating, 2.0 μM of(E)-4-fluorostyryl-4-chlorobenzylsulfone was added to the medium.Following a 24 hour preincubation with the styryl sulfone, the variouscytotoxic agents listed in Table 6 were added to the cells, at theconcentrations given in Table 6. the number of viable cells wasdetermined by Trypan blue exclusion using a hematocytometer 96 hoursafter exposure to cytotoxic agent. The results appear in Table 6. The“Protection Ratio” is the number of viable cells following treatmentwith (E)-4-fluorostyryl-4-chlorobenzylsulfone and cytotoxic agent,divided by the number of viable cells remaining after treatment withcytotoxic agent alone. A protection ratio of 2 or more is consideredhighly significant, while is protection ratio of 1.5-2 is consideredless significant. As shown in Table 6, normal cells were protected bythe styryl sulfone from the cytotoxic effect of mitotic phase cell cycleinhibitors and topoisomerase inhibitors, but not from the cytotoxiceffect of drugs of other classes. TABLE 6 Protective Effect of(E)-4-Fluorostyryl-4-Chlorobenzylsulfone on HFL-1 Cells Treated withCytotoxic Drugs Cytotoxic Drug Protection name conc. μM Drug class Ratiopaclitaxel 0.25 antimitotic 2.5 vincristine 0.25 antimitotic 3.0camptothecin 0.5 topoisomerase I inhibitor 2.1 etoposide 3.0topoisomerase II inhibitor 3.5 mitoxantrone 0.3 topoisomerase IIinhibitor 2.0 doxorubicin 0.4 topoisomerase II inhibitor 1.55-fluorouracil 20 DNA antimetabolite 1.3 cisplatin 5.0 alkylating agent1.3

Example 5 (E)-4-Fluorostyryl-4-Chlorobenzylsulfone Protection of NormalHuman Fibroblasts from Vincristine Cytotoxicity

[0199] HFL-1 cells were treated with 0-250 mM vincristine and,optionally, 2.0 μM (E)-4-fluorostyryl-4-chlorobenzylsulfone either 24hours before or after vincristine treatment, or simultaneously withvincristine treatment. Cell viability was assessed 96 hours after theaddition of vincristine. The results are shown in FIG. 4: “V”,vincristine alone; “A→V”, styryl sulfone followed by vincristine 24hours later; “A+V”, simultaneous styryl sulfone and vincristinetreatment; “V→A”, vincristine followed by styryl sulfone 24 hours later.Pretreatment with (E)-4-fluorostyryl-4-chlorobenzylsulfone conferredprotection from the toxic effects of vincristine.

Example 6 (E)-4-Fluorostyryl-4-Chlorobenzylsulfone Protection of Micefrom Paclitaxel Toxicity

[0200] ICR female mice age 10-12 weeks (Taconic) were divided into thefollowing treatment groups and received intraperitoneal injections of 50mg/Kg (E)-4-fluorostyryl-4-chlorobenzylsulfone dissolved in DMSO and/or150 mg/kg paclitaxel (Taxol, Sigma Chemical Co.) dissolved in DMSO. Thestyryl sulfone was given 24 hours before paclitaxel, 4 hours beforepaclitaxel, or simultaneously with paclitaxel. Control animals receivedpaclitaxel alone or styryl sulfone alone. Mortality was assessed 48 and144 hours after paclitaxel injection. The results are shown in FIG. 5(48 hours post paclitaxel administration) and FIG. 6 (144 hours postpaclitaxel administration). Paclitaxel toxicity in mice is abrogated bypre-treatment with (E)-4-fluorostyryl-4-chlorobenzylsulfone.

Examples 7-12 Antitumor and Cytoprotection Assay of Styryl Sulfones

[0201] A. Antitumor Assay

[0202] The styryl benzylsulfones listed in Table 7, below, were testedfor antitumor activity as follows. A panel of the following humancarcinoma cell lines was plated at a cell density of 1.0×10⁵ cells perwell in six culture plates: prostate tumor cell line DU-145; breasttumor cell line MCF-7; non-small cell lung carcinoma cell line H157; andcolorectal carcinoma cell line DLD-1. The compounds were added to thecultures at a final concentration of 2.5 μM, and 96 hours later thetotal number of viable cells was determined by counting the number ofviable cells, as determined by Trypan blue exclusion, using ahematocytometer. The activity of each compound was determined bycomparing the viable cell number of treated to untreated controls. Theresults appear in Table 7.

[0203] B. Cytoprotection Assay

[0204] The cytoprotective activity of the same styryl benzylsulfones wasdetermined as follows. Normal human HFL-1 cells were plated at a celldensity of 1.0×10⁵ cells per well in six culture plates. Styrylbenzylsulfone was added 24 hours later at a final concentration ofeither 2.0 or 10 μM. The time of styryl sulfone addition was designatedas time zero. Paclitaxel (250 nM) was added at either time zero, or 24hours after time zero. The total number of viable cells was determined,as described above, after 96 hours of paclitaxel treatment. A compoundwas deemed to be active if the number of viable cells following thecombination treatment was higher than the number of cells aftertreatment with paclitaxel alone. The data are set forth in Table 7.TABLE 7 Antitumor and Cytoprotective Effect of Styryl Sulfones Ex.Compound Antitumor Cytoprotection 7(E)-4-fluorostyryl-4-chlorobenzyl + + sulfone 8(E)-4-chlorostyryl-4-chlorobenzyl + + sulfone 9(E)-2-chloro-4-fluorostyryl-4- + + chlorobenzyl sulfone 10(E)-4-carboxystyryl-4-chlorobenzyl − + sulfone 11(E)-4-fluorostyryl-2,4-dichlorobenzyl + + sulfone 122-(phenylsulfonyl)-1-phenyl-3-(4- − + fluorophenyl)-2-propen-1-one

[0205] All references discussed herein are incorporated by reference.One skilled in the art will readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent therein. The presentinvention may be embodied in other specific forms without departing fromthe spirit or essential attributes thereof and, accordingly, referenceshould be made to the appended claims, rather than to the foregoingspecification, as indicating the scope of the invention.

What is claimed is:
 1. A method for protecting an animal from cytotoxicside effects of the administration of a mitotic phase cell cycleinhibitor or a topoisomerase inhibitor comprising administering to theanimal, in advance of administration of said inhibitor, an effectiveamount of at least one cytoprotective α,β-unsaturated aryl sulfonecompound, wherein the mitotic phase cell cycle inhibitor andtopoisomerase inhibitor are other than an α,β-unsaturated aryl sulfonecompound.
 2. A method according to claim 1 wherein the cytoprotectivecompound has the formula I:

wherein: n is one or zero; Q₁ and Q₂, same or different, are substitutedor unsubstituted aryl; or a pharmaceutically acceptable salt thereof. 3.The method according to claim 2 wherein: Q₁ is selected from the groupconsisting of substituted and unsubstituted phenyl, 1-naphthyl,2-naphthyl, 9-anthryl and an aromatic radical of formula II:

 wherein: n₁ is 1 or 2, Y₁ and Y₂ are independently selected from thegroup consisting of hydrogen, halogen, and nitro; X₁ is selected fromthe group consisting of oxygen, nitrogen, sulfur and

 and Q₂ is selected from the group consisting of substituted andunsubstituted phenyl, 1-naphthyl, 2-naphthyl, 9-anthryl and an aromaticradical of formula III:

 wherein: n₂ is 1 or 2, Y₃ and Y₄ are independently selected from thegroup consisting of hydrogen, halogen, and nitro, and X₂, X₃ and X₄ areindependently selected from the group consisting of carbon, oxygen,nitrogen, sulfur and

provided that not all of X₂, X₃ and X₄ may be carbon; or apharmaceutically acceptable salt thereof.
 4. A method according to claim3 wherein Q₁ and Q₂ are selected from substituted and unsubstitutedphenyl.
 5. A method according to claim 4 wherein the cytoprotectivecompound has the formula IV:

wherein: R₁ through R₁₀ are independently selected from the groupconsisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, nitro,cyano, carboxy, hydroxy, phosphonato, amino, sulfamyl, acetoxy,dimethylamino(C2-C6 alkoxy), C1-C6 trifluoroalkoxy and trifluoromethyl;or a pharmaceutically acceptable salt thereof.
 6. The method accordingto claim 4 wherein the cytoprotective compound has the formula V:

wherein R₁, R₂, R₃ and R₄ are independently selected from the groupconsisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, nitro,cyano, carboxy, hydroxy and trifluoromethyl; or a pharmaceuticallyacceptable salt thereof.
 7. The method of claim 6 wherein thecytoprotective compound is selected from the group consisting of(E)-4-fluorostyryl-4-chlorobenzylsulfone;(E)-2-chloro-4-fluorostyryl-4-chlorobenzylsulfone;(E)-4-chlorostyryl-4-chlorobenzylsulfone;(E)-4-carboxystyryl-4-chlorobenzyl sulfone; and(E)-4-fluorostyryl-2,4-dichlorobenzylsulfone.
 8. The method according toclaim 1 wherein the cytoprotective compound has the formula VI:

wherein: R₁, R₂, R₃ and R₄ are independently selected from the groupconsisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, nitro,cyano, carboxy, hydroxy and trifluoromethyl; or a pharmaceuticallyacceptable salt thereof.
 9. The method according to claim 1 wherein thecytoprotective compound has the formula VII:

wherein: Q₃, Q₄ and Q₅ are independently selected from the groupconsisting of phenyl and mono-, di-, tri-, tetra- and penta-substitutedphenyl where the substituents, which may be the same or different, areindependently selected from the group consisting of halogen, C1-C8alkyl, C1-C8 alkoxy, nitro, cyano, carboxy, hydroxy, phosphonato, amino,sulfamyl, acetoxy, dimethylamino(C2-C6 alkoxy), C1-C6 trifluoroalkoxyand trifluoromethyl; or a pharmaceutically acceptable salt thereof. 10.The method according to claim 9 wherein the cytoprotective compound hasthe formula VIIa:

wherein: R₁ and R₂ are independently selected from the group consistingof hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, nitro, cyano, carboxy,hydroxy, and trifluoromethyl; and R₃ is selected from the groupconsisting of unsubstituted phenyl, mono-substituted phenyl anddi-substituted phenyl, the substituents on the phenyl ring beingindependently selected from the group consisting of halogen and C1-8alkyl; or a pharmaceutically acceptable salt thereof.
 11. The method ofclaim 10 wherein the cytoprotective compound is2-(phenylsulfonyl)-1-phenyl-3-(4-fluorophenyl)-2-propen-1-one.
 12. Themethod of claim 1 wherein the cytoprotective compound is of theZ-configuration.
 13. The method according to claim 1 wherein thecytoprotective compound is administered at least about 4 hours beforeadministration of the mitotic phase cell cycle inhibitor ortopoisomerase inhibitor.
 14. The method according to claim 13 whereinthe cytoprotective compound is administered at least about 12 hoursbefore administration of the mitotic phase cell cycle inhibitor ortopoisomerase inhibitor.
 15. The method according to claim 14 whereinthe cytoprotective compound is administered at least about 24 hoursbefore administration of the mitotic phase cell cycle inhibitor ortopoisomerase inhibitor.
 16. The method according to claim 13 whereinthe mitotic phase cell cycle inhibitor is selected from the groupconsisting of vinca alkaloids, taxanes, naturally occurring macrolides,and colchicine and its derivatives.
 17. The method according to claim 13wherein the topoisomerase inhibitor is selected from the groupconsisting of camptothecin, etoposide and mitoxantrone.
 18. The methodaccording to claim 16 wherein the mitotic phase cell cycle inhibitor isselected from the group consisting of paclitaxel and vincristine.
 19. Amethod for treating cancer or other proliferative disorder comprisingadministering to an animal an effective amount at least onecytoprotective α,β-unsaturated aryl sulfone compound followed by aneffective amount of at least one mitotic phase cell cycle inhibitor ortopoisomerase inhibitor after administration of the cytoprotectiveα,β-unsaturated aryl sulfone compound, wherein the mitotic phase cellcycle inhibitor and topoisomerase inhibitor are other than anα,β-unsaturated aryl sulfone compound, and wherein the animal isprotected from the cytotoxic side effects of the administration of saidmitotic phase cell cycle inhibitor or topoisomerase inhibitor.
 20. Themethod according to claim 19 wherein the cytoprotective compound isadministered at least about 4 hours before administration of the mitoticphase cell cycle inhibitor or topoisomerase inhibitor.
 21. The methodaccording to claim 20 wherein the cytoprotective compound isadministered at least about 12 hours before administration of themitotic phase cell cycle inhibitor or topoisomerase inhibitor.
 22. Themethod according to claim 21 wherein the cytoprotective compound isadministered at least about 24 hours before administration of themitotic phase cell cycle inhibitor or topoisomerase inhibitor.
 23. Themethod of claim 19 wherein the cytoprotective compound is selected fromthe group consisting of (E)-4-fluorostyryl-4-chlorobenzylsulfone;(E)-2-chloro-4-fluorostyryl-4-chlorobenzylsulfone;(E)-4-chlorostyryl-4-chlorobenzylsulfone;(E)-4-carboxystyryl-4-chlorobenzyl sulfone; and(E)-4-fluorostyryl-2,4-dichlorobenzylsulfone.